It is known that the immune system, particularly T cells, plays an important role in the elimination of cancer (tumor) by a living body. Indeed, infiltration of lymphocytes exhibiting cytotoxic actions on cancer cells in human cancer foci has been observed (Arch. Surg., 126: p 200, 1990), and cytotoxic T lymphocytes (CTLs) recognizing autologous tumor cells have been isolated from melanomas without great difficulties (e.g., Immunol. Today, 8: p 385, 1987; J. Immunol., 138: p 989, 1987; and Int. J. Cancer, 52: p 52, 1992). In addition, the results of clinical treatment of melanomas by transfer of the CTLs also suggested the importance of T cells in cancer elimination (J. Natl. Cancer. Inst., 86: p 1159, 1994).
Although the target molecules of CTLs attacking autologous tumor cells had long been unclear, such molecules have become clearer gradually as the advance in immunology and molecular biology in recent years. Specifically, it has been revealed that CTLs recognize a complex between a peptide, called cancer antigen peptide, and a major histocompatibility complex class I antigen (MHC class I antigen, also referred to as HLA antigen) through the T cell receptors (TCRs), and thereby attacking autologous tumor cells.
Cancer antigen peptides are generated by intracellular proteasomal degradation of cancer-specific antigen proteins after synthesis in cells. The cancer antigen peptides thus generated bind to MHC class I antigens (HLA antigens) in endoplasmic reticulum to form complexes, and the complexes are transported to the cell surface to be presented as an antigen. Antigen-specific CTLs recognize the complex presented as an antigen, and exhibits anti-cancer effects through the cytotoxic action or production of lymphokines. As a consequence of elucidation of a series of the actions, it has become possible to treat cancer by using cancer antigen protein or a cancer antigen peptide as a so-called cancer vaccine to enhance cancer-specific CTLs in the body of a cancer patient.
As a cancer antigen protein, T. Boon et al. identified a protein named MAGE from human melanoma cells for the first time in 1991 (Science, 254: p 1643, 1991). Subsequently, several additional cancer antigen proteins have been identified mainly from melanoma cells. Examples of melanoma antigens that have been identified are melanosomal proteins such as a melanocytic tissue-specific protein, gp100, MART-1 and tyrosinase, MEGE-related proteins that are expressed not only on melanomas but also on various cancer cells and normal testicular cells; β-catenin having a cancer-specific amino acid mutation; and CDK4. Cancer antigen proteins other than those from melanomas have also been identified including products of oncogenes such as HER2/neu and p 53 (variant); cancer markers such as CEA and PSA; and viral proteins such as HPV and EBV. Detailed descriptions of these substances can be found in published reviews (e.g. Immunol. Today, 18: p 267, 1997; J. Exp. Med., 183: p725, 1996; and Curr. Opin. Immunol., 8: p 628, 1996).
Livin has been identified as a molecule belonging to an inhibitor of apoptosis protein (IAP) family (J. Biol. Chem. 276: p 3238, 2001). Livin consists of 280 amino acids and has a singe unique repeated sequence of about 70 amino acids called a baculoviral IAP repeat (BIR). ML-IAP (melanoma inhibitor of apoptosis protein) which is a molecule identified as an IAP highly expressed by melanomas around the same time has the same amino acid sequence as livin (Curr. Biol. 10: p 1359, 2000).
It was reported that T cells isolated from metastatic focus of melanoma of an HLA-A*0201-positive patient recognized ML-IAP-derived peptides and exerted cytotoxic activity, and hence livin was presumed to be a target of cytotoxic T cells (CTLs) as a cancer antigen protein (Proc. Natl. Acad. Sci. USA, 100: p 3398, 2003). However, it has not been elucidated whether or not livin contains a peptide portion(s) capable of binding to HLA-A24 antigen among a number of HLA antigens.